Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
View Patent ↗The present invention relates to novel heterocyclic compounds which are useful for inhibiting glycogen synthase kinase 3 (GSK-3), methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
1. A heterocyclic compound of the general formulae IA or IB
a stereoisomer, N-oxide, tautomer and/or physiologically tolerated acid addition salt thereof; or a compound of the general formulae IA or IB, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope,
wherein
X 1 , X 2 , X 3 and X 4 are independently of each other selected from the group consisting of CR 1 and N;
each R 1 is independently selected from the group consisting of hydrogen, cyano, NR a R b , OH, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -halocycloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, formyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, COOH, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, C 1 -C 6 -alkyl-NR a R b , CO—NR a R b , an aromatic radical Ar, which is selected from the group consisting of phenyl and a 5- or 6-membered N- or C-bound heteroaromatic radical containing 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N as ring members, wherein Ar is unsubstituted or carries one or two radicals R 7 and wherein Ar may also be bonded via a CH 2 group, and a saturated or partially unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic radical containing 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, wherein the heterocyclic radical is unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
R 2 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -haloalkenyl, OH or F;
R 3 and R 4 form together a bridging group —(CH 2 ) m —, wherein m is 3, 4 or 5, where 1, 2 or 3 of the CH 2 groups may be replaced by a group or a heteroatom selected from the group consisting of CO, O, S, SO, SO 2 , NR c and NO, and where 1, 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R 8 ;
R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and NR a R b ;
each R 7 is independently selected from the group consisting of halogen, OH, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, NR a R b , C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, CO—NR a R b , a phenyl group, and a saturated, partially unsaturated or aromatic 5- or 6-membered heterocyclic radical containing 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, wherein phenyl and the hetero-cyclic radical are, independently of each other, unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy, or in the hetero-cyclic ring two geminally bound radicals may together form a group═O;
each R 8 is independently selected from the group consisting of halogen, OH, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, NR a R b , C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, CO—NR a R b , a phenyl group and a saturated, partially unsaturated or aromatic 3-, 4-, 5-, 6- or 7-membered heterocyclic radical containing 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, wherein phenyl and the heterocyclic radical are, independently of each other, unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
R a and R b are independently of each other selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -haloalkoxycarbonyl; or
R a and R b form, together with the nitrogen atom to which they are bonded, a 3-, 4-, 5-, 6- or 7-membered saturated or unsaturated aromatic or non-aromatic N-heterocyclic ring, which may contain 1 further heteroatom or heteroatom-containing group selected from the group consisting of N, O, S, SO and SO 2 as a ring member, where the N-heterocyclic ring may carry 1 or 2 radicals selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; and
each R c is independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -haloalkoxycarbonyl.
2. The heterocyclic compound of claim 1 , wherein
the CH 2 unit bound in the position of R 3 is not replaced by a NR c group.
3. The heterocyclic compound of claim 1 , wherein R 3 and R 4 form together a bridging group —(CH 2 ) m —, wherein m is 3, 4 or 5, where 1 or 2 of the CH 2 groups may be replaced by a group or a heteroatom selected from the group consisting of CO, O and NR c , and where 1 or 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R 8 .
4. The heterocyclic compound of claim 1 , where m is 3 or 4.
5. The heterocyclic compound of claim 3 , where the bridging group is selected from the group consisting of —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 OCH 2 —, —NR c CH 2 CH 2 —, —CH 2 CH 2 NR c —, —CH 2 NR c CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —OCH 2 CH 2 CH 2 —, —CH 2 OCH 2 CH 2 —, —CH 2 CH 2 OCH 2 —, —CH 2 CH 2 CH 2 O—, —NR c CH 2 CH 2 CH 2 —, —CH 2 NR c CH 2 CH 2 —, —CH 2 CH 2 NR c CH 2 —, —CH 2 CH 2 CH 2 NR c —, —C(═O)CH 2 CH 2 CH 2 —, —CH 2 C(═O)CH 2 CH 2 —, —CH 2 CH 2 C(═O)CH 2 — and —CH 2 CH 2 CH 2 C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R 8 .
6. The heterocyclic compound of claim 5 , where the bridging group is selected from the group consisting of —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 OCH 2 —, —CH 2 NR c CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —OCH 2 CH 2 CH 2 —, —CH 2 OCH 2 CH 2 —, —CH 2 CH 2 OCH 2 —, —CH 2 CH 2 CH 2 O—, —CH 2 NR c CH 2 CH 2 —, —CH 2 CH 2 NR c CH 2 —, —C(═O)CH 2 CH 2 CH 2 —, —CH 2 C(═O)CH 2 CH 2 —, —CH 2 CH 2 C(═O)CH 2 — and —CH 2 CH 2 CH 2 C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R 8 .
7. The heterocyclic compound of claim 6 , where the bridging group is selected from the group consisting of —CH 2 CH 2 CH 2 —, —CH 2 NR c CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 NR c CH 2 CH 2 —, —CH 2 CH 2 NR c CH 2 —, —C(═O)CH 2 CH 2 CH 2 —, —CH 2 C(═O)CH 2 CH 2 —, —CH 2 CH 2 C(═O)CH 2 — and —CH 2 CH 2 CH 2 C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R 8 .
8. The heterocyclic compound of claim 1 , where the radicals R 5 and R 6 are hydrogen.
9. The heterocyclic compound of claim 1 , where each R 8 is independently selected from the group consisting of halogen, OH, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, NR a R b , C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -haloalkoxycarbonyl.
10. The heterocyclic compound of claim 9 , where each R 8 is independently selected from the group consisting of OH, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy.
11. The heterocyclic compound of claim 1 , where R c is hydrogen or C 1 -C 6 -alkoxycarbonyl.
12. The heterocyclic compound of claim 1 , where all of X 1 , X 2 , X 3 and X 4 are CR 1 or one of X 1 , X 2 , X 3 and X 4 is N and the others are CR 1 .
13. The heterocyclic compound of claim 12 , where all of X 1 , X 2 , X 3 and X 4 are CR 1 .
14. The heterocyclic compound of claim 13 , where X 1 , X 2 and X 4 are CH and X 3 is CR 1 .
15. The heterocyclic compound of claim 14 , where X 3 is CR 1 , wherein R 1 is H, CN or COOH.
16. The heterocyclic compound of claim 1 , where R 2 is hydrogen.
17. The heterocyclic compound of claim 1 , where R 2 is C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 2 -C 4 -alkenyl or fluorine.
18. The heterocyclic compound of claim 1 , of the formulae IA-1 or IB-1
19. The heterocyclic compound of claim 1 , wherein at least one hydrogen atom has been replaced by a deuterium atom.
20. A pharmaceutical composition comprising:
at least one heterocyclic compound as defined in claim 1 , a stereoisomer, N-oxide, tautomer and/or physiologically tolerated acid addition salt thereof, or at least one heterocyclic compound as defined in claim 1 wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope; and
at least one physiologically acceptable carrier.
21. The heterocyclic compound of claim 14 , where X 3 is CR 1 , wherein R 1 is CN.
22. The heterocyclic compound of claim 1 , or a stereoisomer, N-oxide, tautomer and/or physiologically tolerated acid addition salt thereof, selected from the group consisting of:
3-(5-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile;
2-oxo-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)indoline-5-carbonitrile;
2-hydroxy-3-(5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile;
2-hydroxy-3-(8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile;
3-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2-oxoindoline-5-carbonitrile; and
3-(5-methoxy-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile.